DESCRIPTION: The overall goals of the proposed research are to understand how transmitter-gated ion channels function, and the mechanisms by which cellular control processes and pharmacological agents modulate receptor function. To reach these goals, it is necessary to determine the steps and rates in receptor activation, to determine which rates are altered in cases in which function is altered, and to determine the likely structural bases for drug binding and actions. The proposed research focuses on the nicotinic acetylcholine receptor (AChR). Biophysical techniques will be used to study receptor function, biochemical techniques to study receptor structure, and molecular biological techniques to alter receptor structure. Continuing studies will utilize the muscle AChR to define the molecular features of the receptor which are involved in determining the channel opening rate. Additional projects will extend the research to neuronal AChRs, of which the functional properties and physiological roles are poorly understood. The research should provide basic information on the function of nicotinic receptors, and the mechanism by which pharmacological agents and cell processes affect function.